Detergent germicidal compositions and process of making the same



, W Pa nique.

14.0mm. or. 251-10 1 This invention relates to a process for the preparation of germicidal detergents andto germicidal detergents obtained by this process and more particularlyto'detergent compositions which combine the detergent properties of ordinary soaps and nonsoap detergents, with the germicidal properties ofN-substituted thiuram sulfides, and to a process of preparing such detergents,

The normal human skin is the habitat of millions of bacteria, the majority of'which are beneath-the surface of the' skin; Of the forty million bacteria usually found on and in the skin of the two handsand arms to the elbows, only about one million are transients residing on the skin stuface';*tlie"remaifiderare resident bacteria and reside insubsurface skin layers. Transient I bacteria are readily removed mechanically by ordinay soap. Resident bacteriaare usually removed only following attack by a satisfactory degerm'ining-agen t; whoseefiectiveness is due to-;its absorption by the skin so that it is -available': to act continuously on bacteria present in the subsurface layers, thereby preventing their multiplicationto any appreciable degree.

It is forthisreason that germicidal soaps which have recently been placed on the market have found a wide application: Such soaps contain a small amount of .a germicidal agent and the-use of the soap; in daily washings provides suflic'ient germicid efto keep thebacterial J count at a practical minimum. In fact, the'bacterial 2,921,899 r' atented Mar. 8, 1960 development of these compounds, the discovery of another germicide which could be combined eflectively with soap would be quiteunexpected In accordance with the instant invention a germicidal detergent soap is provided comprising as a germicidal agent a thiuram sulfide having each thiuram nitrogen atom fully substituted withaliphatic groups, and a compound which acts as-a stabilizer for the thiuram sulfide. This stabilizer is a compound of a group IVa element below silicon andin a valence state of more than two. At concentrations appreciably. lessthan would be used in the case of hexachlorophene (2,2f-dihydroxy-3,5,& 3,5,6-heXachloro diphenyl methane), such thiuram sulfides are capable. of producing germicidally potent soap compositions. I

'The'compositions. of the invention are more active against gram-negative organisms s'uclr as Escherichia coli than hexachlorophene soaps and are more substantive to p the skin than hexachlorophene soaps. The soaps of the invention lack ofiensive odors; The low cost and availability of these thiuram sulfides favorably distinguish count can be lowered to a point at which it equalsoriis for efiective germicidal action, hexachlorophene' germicidal soaps have to be-marketed-at aprice differential -compared t o ordinary soaps.

J In additionto the 2;2 -dihydroxy;halogenated diphenyl methanes, various phenolic materialshave beencombined withsoap, but; because of the generally recognized depressing: action of soap upon the; bactericidal properties of germicidal agents,germicidal-soaps have not been obtained. This point has; been efiectively demonstrated byiKunza-ndljump andis' reviewed in-- some. detailat columns- ,3 and ofltheir US: Patent No. 2,5;3550177, dated-December; 26, L 1950 Although the: 2,-2-'-di-hydroxy halogenated diphenyl; methanes arewanting in some re spects}; may have been recorded as.;u nique: in= that (their germicidal; potency, is relatiyelyunafiected bw, soap. In;

View of the very considerable research" which led to the them from othergerrnicides.

The term thiuram sulfide is inclusive ofthiuram monosulfides, disulfides, trisulfides, tetrasulfides and h'exasulfides. I

The aliphatic thiuram sulfides used as a germicidal agent in the soap; compositions of the invention have the following formula:

n has the value of one to six, and Z5 and Z each are selected from the group consisting of a single bivalent cycloaliphatic radical and two monovalent aliphatic radicals. The number of carbon at0ms 'is-not critical, but the antibacterial activity tends to decrease, as the number of carbon atoms increases, and therefore Z and Z preferably have from" twoto'eightcarbon atoms.

:When Z and/or 2 arev bivalentataken with the thiuram nitrogen atom they form a saturated or unsaturated heterocyclic rin'g'in which the thiuram nitrogen atom is one of the ring atoms.- A typical heterocyclic radical of this type ispiperidine. i a

When Z and/0r Z are monovalent, they can be selected from the group consisting of saturated and unsaturated straight and branched chainaliphatic radicals, preferably having from one to four carbon 7 atoms. Among those which can' be employed' are ethyl, methyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, sec.-butyl, butadiene, butylen'e and propylene. Alkyl radicals having from one to two carbonatoms; are. preferred.

Typical aliphatic thiuram monosulfides coming within the invention are:

m C H a H m H C 3 S S r a. N t H\ a a H H "H m H H w m H H C C m m i MW H H m m H H C/\C J B T N r H\ /H C C H H "a MN m H C C CHaCECOHa GHs CAHD

our-or an} OzHn N-G-SS-SS-SS-C-N Cs g N--OS-- The aliphatic thiuram sulfides are known classes of materials, and their preparation is set forth in the litera- For the most part they are insoluble in water, soluble in alcohol, acetone and benzene, and very soluble roforrn and carbon disulfide. In the quantities in they are employed in soaps, they do not produce irritation, are not toxic, and are compatible with the usual soap components, including neutral salts, perfume; opacifiers and small amounts of carbonates.

The term soap as used herein refers to .alkali metal saturated and unsaturated higher fatty ng from about eight to about twenty-six carhon atoms, such as capric, caprylic, lauric, myristic,

palmitic, stearic,- oleic, linoleic, linolenic, arachidic, behenic, margaric, tridechoic, and cerotic acids and the mixtures of such acids naturally occurring in fats, oils, d rosins, such as the soaps of coconut oil fatty g5 acids, tallow fatty acids, pig fat, fish oil fatty acids,

beeswax, palm oil fatty acids, sesame oil fatty acids,

peanut oil fatty acids, olive oil fatty acidsypalm kernel oil fatty acids, cottonseed oil. fatty acids, soyabean oil fatty acids, corn oil fatty acids, 'babas'su oil fatty acids, rosm acids, abietic acid, and greases.

Only small amounts of thiuram. sulfide are required need to employ more than is required to give the desired germicidalelfect, and in generalffor-thi's reason from 0.2 to 2.0% would be preferred; Increasing the concentration of thiuram sulfide beyond 5% further increases the costJof the soap and might tend to reduce the detergent properties of the. composition. At unnecessarily high concentrations thereis a possibility ofi skin irritation due to the. thiuram sulfide. It will readily be seen that the thiuram sulfide concentration isnot critical but. would be determined from a consideration. offthese It has been found free alkali must be eliminated from the thiuram sulfide-stabilizing compound-soap composition]. This may be accomplishedgif the stabilizing 1 compound is acidic, by addition of a sufiicient additional amount oft'he stabilizing compound Where necessary to take up all of the free alkali. poundis not acidic, then free acid is'added in the amount required to take up all of the free alkali. As the acid, there canbe used an inorganic acid, such as boric acid, or an acidic inorganic salt, such as sodium bicarbonate, or an organic acid, including the long and short chain aliphatic acids, especially the free soap acids of which the soap is formed, e,g.,'stearic, myristic, and palmitic acids, 'or mixtures of any of these. v

For example, in the case of a hydrosulfite-treated soap containing a standard 0.05% free alkali and tetramethyl thiuram disulfide, anaddition of 0.05% stannic chloride by Weight of the soap will elimin'ate'free alkali and produce a product having a stability against odor and factors, as long as enough isjused to give the. desired containing 0.2% of stannic chloride will have a stability antibacterial effect.

When exposed to high temperatures for long periods o f'time or over long periods of storage even at ordinary temperatures thiuram sulfide in a soap composition. shows a tendency to decompose. The decomposition products are "unknown but appear to include complex sulfur compounds, amines, carbon disulfide, and mercaptans. These materials lead to the development of anundesirable and in some cases an'exceedingly unpleasant odor. Reactive sulfurfbearing compounds appear also to be available, because if a soapcontai'ning thefdecomposition products of thiuram disulfide comes into contact with copper ion a dark colored sulfur compound or copper is, formed, insoluble in water, resulting in'a dark colored stain which.

can be removed by customary cleaning methods or by treatment with acid butwhichit is desirableto avoid if possible. .In accordance with the invention, therefore,

As-a. source of stannic ion, stannic chloride: SnCL; is

preferred. Stannic salts of both inorganic and organic acids can be employed, for example, stannic sulfate, stan nic hydroxide sulfate, Sn(0H), SO ,stannic oxalate and stannic tartrate. It would of course be preferable to employ a compound which is water-soluble and which will itself produce no color in the bar, if it is important that the soap be white. The stannic ortho and meta (0t and ,8) acids can also be employedand these can'be used either as the acid, H SnO H SnO H Sn 'O or as the metal salts thereof, such as sodium stannate, potassium stannate and ammonium stannate.

In general, it can be said that any amount of the stabilizingcompound will improve the stability of the v thiuram sulfide soap against odor and. staining, and the amount which would be employed therefore will depend upon the storage stability which is required.v It may be observed that in the cases where the soap, because of prior processing methods, contains reducing agents, for example, hydrosulfite addedin the kettle to bleach the soap, it is necessary to employ a supplemental amount of the stabilizingcompound'to function as an oxidizing agent to destroy such reducing agents' of up to onehour without disadvantage.

staining of at least two months, while a hydrosulfitetreated low free alkali tetramethyl thiuram disulfide soap against odor and staining of over one year under ordinary room temperatures, including the highest temperatures which would be experienced under summer conditions. Such soap compositions have been formed intobars after being subjected to temperatures up to 125 F. for periods When a stabilizing compound is incorporated in these soap compositions, it isimportant that all of the ingredients be added beforetthe thiuram sulfide, and that the thiuram sulfide be thoroughly dispersed in the soap mixture. Mixing of the batch should not be continued beyond the point at which the thiuram sulfide "is thoroughly dispersed.

While several mixing procedures will be apparent to those skilled in the art in order to achieve this result, the following procedure is recommended: The soap. chips are weighed. into the mixer and followed immediately "by addition of the stabilizing compound, for example, stannic chloride. The stabilizing compound can be added in the form of a solution or dispersion in water, in which the concentration of the'compcund is not critical. Mixing is continued'for a sufiicient. time to insure thorough disper- V sion of the compound in the soap.- The remaining components of the mix, for example, perfume and dye, are; i

. added, in the form ofasolution if desired, as quickly as "possible and mixing is continued again for a long enough period to insure a thorough dispersion. Thereafter the 3 hiuram sulfide is added with complete and adequatemix- .ing only for the time to insure uniformity of dispersion.

The final mix then can be treatedin the conventional ways to produce the desired soap. To form a bar, for example, the mix can be plodded and extruded using conventional equipment.

The thiuram sulfide soaps in accordance with the invention can-be formed as bar soaps, powdered soaps, chip soaps, flake'soaps, bead soaps, bar and cake soaps and soap compositions intended for. toilet, washing and disinfectant purposes in addition to their use as detergents.

There is no upper limit 'to the amount of stabilizing compound which-can be used. Amounts within the range of 0.05 to 2% have been found to give adequate inhibition of odor formation and staining, but as much as 5% is not disadvantageous, although usually unneces sary and therefore not economical. Even more than 5% canbeused. t

'drying is convenient in many instances.

The compositions can be dried in any desired way; spray It is, desirable to hold the temperature to which the mix is subjected during conversion into its final form "below the temperature at which the thiuram sulfide would be decomposed.

Soap mixtures in accordance with the invention have been I If the stabilizing com .sixty seconds.

.7 Test and the Skin- Disc Test (a modification of the Zone .Reduction Test). Details of these tests follow:

(1) The Serial Basin Ha ndwashing T est.-This test ;determines the skin bacterial flora at various time intervals as brought about by the continuous use of germicidal soap over a two week period or more. At least six individual subjects are used as a panel in each test. Two types of soap are used in the test, the germicidal soap employed daily for the two week test period and the plain soap used where the wash water is collected in various basins for determining the counts of bacteria removed.

The subject exposes the arms up to the elbow, and 2000 cc. of lukewarm tap waterare run into the sterilized first basin, the bacterial count of the water being determined by removing two 1 cc. samples which are-added to 15 to 18 cc. of nutrient agar. The subject moistens the hands up to the wristline, then applies plain soap for fifteen seconds followed by thorough lathering for The hands are rinsed thoroughlyfor fifteen seconds into the basin.

Two more similar washings are carried out successively under the tap, the area covered extending almost to the elbows, and the water is discarded.

The subject then moves to the second basin containing 2000 cc. of lukewarm tap water and carries out the washing procedure exactly as in the first basin.

The subject then moves to the third basin andrepeats the washing procedure of basins 1 and 2.

Two 1 cc. of samples of 2000 cc. WfiSh'WfliCl. in each -basin are removed using a sterile pipette and added to 15 cc..of nutrient agar in sterile Petri dishes. This is agitated, allowed to cool and harden and incubate at 37 C. for forty-eight hours. At the end of this time the number of colonies present are counted and the counts multiplied by 2000. V

The above test is repeated at intervals over the two weeks test period. The percent reduction in bacterial count is computed on the basis of the reduction in count of the 2nd and 3rd basin wash waters.

(2) The Zone Reduction Test.This test measures the inhibitory effect of an 8% 1 solution within the zone of direct contact of the solution with the bacteria-seeded agar. A range of dilutions is investigated to determine the minimum concentration of germicide in the soap solu- -tion required to effect a strong reduction in the bacterial count in the agar in direct contact therewith. An 8% 1 .solution of the soap is used since this is approximately the concentration of soap found in lather.

For use in the test, cultures of Staphylococcus aureus and Escherichia coli are maintained on nutrient broth with transfers made daily. In preparing the agar plates, 0.1 ml. of a twenty-four hour nutrient broth culture of the test organism'is mixed thoroughly into 15 ml. of melted nutrient agar, which is then poured into a Petri plateand permitted to harden.

Filter paper discs (0.5 inch in diameter) prepared from Whatman filter paper No. 2 are placed on the hardened agar circularly (about 0.75 inch from the periphery).

Each disc is wetted carefully with one measured drop of the 8% solution of a test soap, using a syringe (25 gauge needle). Six or seven discs can be arranged on each seeded agar plate, including the control plain soap. Duplicate plates are prepared and are incubated for twenty-four to forty-eight hours at 37 C.

In counting the plates, the filter discs are carefully removed with forceps and the zones of disc Contact are examined microscopically (100x) with replicate counts made offields' selected at random. To facilitate counting, a Howard micrometer disc (No. 823) can be inserted into the ocular piece (X five fields of three adjacent squares are counted and the average field count determined.

The antibacterial potency of a test soap solution is v 3 Basis soap weight.

expressed in terms of a Bacteriostatic Index" which is computed from the average zone readings as follows:

Bacteriostatic Index Av. zone'count. of test soap Av. zone count of control soap Index:

The test is a simple, convenient and direct method of determining bactericidal activity, and compositions which show strong activity at low concentrations under the conditions of the test have proved to be effective in actual handwashing tests with human subjects.

(3) The Skin Disc Test (a modification of the Zone Reduction Test).D ehydrated calf skin discs are used instead of filter paper discs. These are rehydrated in sterile water for fifteen minutes and then placed in test tubes with 25 cc. of the 8% 1 test solutions and shaken for fifteen minutes. At the end of this time, the soap solutions are drained from the discs and sterile water added. The discs in the sterile water are shaken for fifteen minutes with a frequent change of water and then placed on the inoculated agar as in the Zone Reduction Test;

The compositions prepared in accordance with the invention have shown excellent germicidal effectiveness when subjected to these tests. 7

The following example illustrates the invention:

Soap chips (750 lbs.), formed from a charge of tallow and 20% coconut oil, bleached by the addition of sodium hydrosulfite Na s- 0 and containing 0.05% free alkali, were weighed into the mixer, following which 1 lb. 8 oz. of stannic chloride was added at once as a 50% solution in water. Mixing was continued for five minutes after which 5 lbs. 13 oz. of perfume and dye were added over a period of one minute and mixing continued for three minutes. Tetramethyl thiuram disulfide (7 lbs. 11 oz.) was added by spreadingit over the surface of the mix and mixing was continued for'not more than four minutes. At the end of this time the tetramethyl thiuram disulfide was found to be thoroughly dispersed in the soap. The mix was transferred to a refiner where it was extruded through screens into another extruder and then into a plodder and formed into bars, all at temperatures between and 9 F.

Any of the above-mentioned thiuram sulfides and/or stabilizing compounds can be substituted for the tetramethyl thiuram disulfide and SnCL; with satisfactory results.

The soap bars obtained were packed in an inner wrap of glassine paper and an outer carton of white patent coated board and subjected to storage at ordinary room temperatures for nine months. No change in the product was noted, whereas in the case of a soap containing thiuram sulfide but no stannic chloride, prepared exactly as set forth, yellowing of both the glassine and the board .was observed, due probably to sulfur compounds formed by decomposition of the tetramethyl thiuram disulfide. The aged product containing the stannic salt had no odor and did not produce stains in the presence of copper ion, whereas the product which did not contain the stannic salt did produce such stains and had a strong odor.

It has been postulated that the decomposition of the 1 Basis soap weight.

wait- 4..

v very sensitive to hydroxyfion.

The carbon disulfide, dirrieth lhr'ni'neand' other decomposition products of dithiocar'bamate, would be responsible for an off odor thep'roductl A reducing agent'such as hydrosulfife or'sulfit'e might CH3 (5) From Equation 5 it can be seen that one molecule of hydrosulfite can be responsible for the decompositions to the dithiocarbam'ate state of three molecules of tetramethyl thiuram disulfide and that the decomposition is It is thought that the stabilizing compound inhibits decomposition of thethiuram sulfide by serving as an electron acceptor and by destroying 8 0; and 80 ions. The role of free acid is to take up hydroxyl ion and thus inhibit Reactions3; 4 and 5. c I

It is known thatgthiuram sulfid e forms the dithiocarbamate in alkaline aqueous solution by hydrolysis or in any aqueous solution in the presence of a reducing agent. (Germs or bacteria may act as reducing agents.) In use it is not clear whether the germicidal properties of the soap are due to the thiuram sulfide or to the dithiocarbamate, but it is not important to establish this since both are present in soap solutions. Dithiocarbamate has been found to enjoy but a transitory existence in soap compositions,.and therefore in order to preserve its activity in soap solutions which are subsequently prepared from the compositions, should it be the'germicidal agent in the soap solution as used, the thiuram sulfide is kept from forming the dithiocarbamate in the soap, but not in the solution, by the stabilizing compound of the invention.

The free alkali is determined in accordance with the following procedure: The soap, before addition of dye, thiuram sulfide and stabilizing agent, is weighed out in a 250 ml. extractionflask on a triple beam or torsion balance, 12.4 gms. in the case of soap chips or fine soap, i.e., soaps of higher fatty acids, 31 gms. in the case of framed soaps and pansamples, i.e., soaps of about 63% fatty acids. To the soap is added approximately 100 ml.

chips and fi'ne soaps; The color change is not very definite for the latter and is recognized in a change of color rather than a disappearance. A blank determination is made on 100 ml. of-the'neutralized alcohol for each batch When N /IO solutions are used, and the volumes of acid or alkali required for neutralization are noted. The calculation then is carried out according to the following equations:

For soap chips and finesoaps' Ml. N/lO acid-(corrected) X 0.0031 X 100 ml. N/IO acid 0.025= percent Na O For framed soaps and pan samples ac d???) 00775 100 p N320 =peroent N320 ml. N /4 acid 0.025= percent Na O The compositions of the invention meet all of the requirements for germicidal soaps, as is evident from tests which have been carried'out on them, and are indistinguishable in appearance from ordinary soaps, They can be used as ordinary detergent soaps and are especially recommended for uses in which both detergent and deg'erming characteristics are desired. The test results show that the compositions used routinely for a period of from one to two weeks lower the bacterialfiora of the skin to a; very low level, equivalent to that obtainable by means of the standard hospital; scrub-up operation. Thercom- '35 positions are particularly valuable for routine surgical and hospital use and generally useful in the prevention of infections arising from skin bacteria.

Those skilled in. the art will perceive many variations in the compositions of the invention. For example, the aliphatic thiuram sulfide need not be the only germicidal agent; other germicides, such as 2,2'-dihydroxy halogenated diphenyl methanes, can be included, for example, if desired. J V The soap compositions, in addition to the soap and germicide, will also usually contain fillers, coloring mate rials and perfumes, as desired, as is familiar to those skilled in the art.

The compositions containing the thiuram sulfide may contain mixtures of detergents, such as soap and an anionic nonsoap, or soap and a nonionic nonsoap. Typical satisfactory anionic nonsoaps are the alkyl sulfates,

typified by sodium lauryl sulfate, known in the trade as Duponol C, the alkyl aryl sulfonates, typified by the sodium polypropylene benzene or toluene sulfonates, and the sodium keryl benzene or toluene sulfonates, the sulfated ethoxynated phenols, typified by the ammonium." salt of sulfated ethoxynated nonyl phenoL prepared by condensation of nonyl phenol with five moles of ethglycol ethers of alkyl phenols, typified by the condensation product of octyl andnonyl phenol with five to twelve moles of ethylene oxide, and the higher fatty acid esters of neutralized alcohol and several glass beads and the 1 soap is dissolved completely in the alcohol by boiling gently on a hot plate under a reflux air condenser. One

of sorbitan-ethylene oxide condensates, such as sorbitan monostearate ester of polyoxyethylene glycol. They may be in any of the forms described heretofore, including cakes or powders, and may include various fillers, sudsing agents and ingredients conventionally employed in detergent formulations. They may be compounded for various tion Serial No. 397,001, filed December 8, 1953, now

abandoned.

I claim:

1. A germicidal detergent composition substantially free from free alkali comprising soap, a germicidal amount of a thiuram sulfide having the formula:

where n is an integer from one to six and Z and Z are hydrocarbon radicals having from two to eight carbon atoms and are selected from the group consisting of a single bivalent cycloaliphatic radical and two monovalent aliphatic radicals, and a tin compound in avalence state higher than two in an amount to stabilize the detergent composition against decomposition of thiuram sulfide as evidenced by the development of odor and staining characteristics.

2. A germicidal detergent soap comprising soap substantially free from free alkali, a compound of tin in a valence state higher than two, said compound being in an amount to stabilize the detergent composition against decomposition of thiuram sulfide as evidenced by the development of odor and staining characteristics, and a germicidal amount of an N-tetramethyl thiuram sulfide.

3. A germicidal detergent soap comprising soap substantially free from free alkali, a compound of tin in a valence state higher than two, said compound being in an amount to stabilize the detergent composition against decomposition of thiuram sulfide as evidenced by the development of odor and staining characteristics, and a germicidal amount of N-tetramethyl thiuram monosulfide.

4. A germicidal detergent soap comprising soap substantially free from free alkali, a compound of tin in a valence state higher than two, said compound being in an amount to stabilize the detergent composition against decomposition of thiuram sulfide as evidenced by the development of odor and staining characteristics, and a germicidal amount of N-tetramethyl thiuram disulfide.

5. A germicidal detergent composition in accordance with claim l in which the thiuram sulfide is present in an amount within the range from 0.01 to about 5 6. A germicidal detergent composition in accordance with claim 1 in which n has the value of one.

7. A germicidal detergent composition in accordance with claim 1 in which n has the value of two.

8. A germicidal detergent composition in accordance with claim 1 in which the stabilizing compound is a stannic salt.

9. A germicidal detergent composition in accordance with claim 8 in which the stannic salt is stannic chloride.

10. A process of forming a germicidal detergent composition comprising dispersing in soap a tin compound in a valence state higher than two in an amount to stabilize the detergent composition against decomposition of thiuram sulfide as evidenced by the development of odor and staining characteristics, and then dispersing therein a germicidal amount of a thiuram sulfide having the forwhere n is an integer from one to six and Z and Z are hydrocarbon radicals having from two to eight carbon atoms and are selected from the group consisting of a single bivalent cycloaliphatic radical and two monovalent aliphatic radicals, including adding an acid-reacting compound if necessary to eliminate free alkali and form a composition substantially free from free alkali.

v .11. A process in accordance with claim 10 in which the stabilizing compound is acid-reacting, and is added in an amount to eliminate free alkali in the final com- 12. A process in accordance with claim 10 in which the acid-reacting compound is an inorganic acid.

13. A process in accordance with claim 10 in which the acid-reacting compound is an inorganic acid-reacting salt. V 14. A process in accordance with claim 10 in which the acid-reacting compound is an organic acid.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES British Medical Journal, June 17, 1944, Vol. 1, pp. 803-806, article by Gordon. 

1. A GERMICIDAL DETERGENT COMPOSITION SUBSTANTIALLY FREE FROM FREE ALKALI COMPRISING SOAP, A GERMICIDAL AMOUNT OF A THIURAM SULFIDE HAVING THE FORMULA: 